KARINE BASTARD · Simulation studies of the relationship between ligand induced rearrangements of enzyme loops and high ligand selectivity

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Project objective

Enzymes are fascinating macromolecules because they present high specificity toward their physiological substrates and in the same time they show high flexibility during catalysis. In particular, experimental studies evidenced the role of loop dynamics in the binding affinity and specificity of the substrate. Such conformational changes on loop would be induced by ligand approach. The objectives of the project are to understand the induced-fit mechanism upon ligand binding and to characterize the tight link between loop rearrangements during association and high ligand selectivity using theoretical approaches. Loop movements generally cover time scales not reachable by classical molecular dynamics simulations. Consequently, we will need to define a novel pro tocol inspired from advanced molecular dynamics, successfully used in simulations of protein folding. This work will build upon expertise in the outgoing laboratory and will be carred out on selected glycosidases studied experimentally and theoretically in the return laboratory. Results will be compared to those obtained by a new robotics method developped in the return laboratory and able to simplify large-scale motions by geometric analysis. Enhancing our knowledge of the induced fit mechanism should be v ery useful to enzyme engineering, since loop movement is often a key element of enzyme activity. Controlling loop flexibility during association should permit to design or alter enzyme function.

Original text from CORDIS.

Participants

• Centre National de la Recherche Scientifique (CNRS) · PARISCoordinatorFrance
• STANFORD UNIVERSITY SCHOOL OF MEDICINE · STANFORDCity levelUnited States
• UNITÉ BIOTECHNOLOGIE, BIOCATALYSE, BIORÉGULATION (U3B) - UFR SCIENCES ET TECHNIQUES NANTES · NANTESCity levelFrance

Links

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